Active principle for mitigating undesired medical conditions

ABSTRACT

A composition for treating or preventing inflammatory-related conditions includes as an active principle a carrier which exhibits a plurality of a scavenger structure capable of mitigating the activity of a mediator of inflammatory-related conditions. The scavenger structure includes a nucleophilic center complying with the formula X 1 (—R″—)(—R′) m H n  where: a) X 1  is a single-bonded heteroatom selected amongst N, O and S and exhibits a free electron pair; b) m is 0 or 1 and n is 1 or 2; c) —R″— is a bivalent organic group providing attachment to the carrier via one of its free valences and to X 1  at the other free valence; and d) R′— is a monovalent organic group attached to the X 1  via its free valence. A method for treating or preventing inflammatory-related conditions in an individual suffering from such conditions includes: providing the composition; and contacting the mediator within or separate from the individual.

TECHNICAL FIELD

The present invention relates to a method and a composition forcombating mediators of the inflammatory cascade of an individual. Themethod is primarily intended for treating and/or preventinginflammatory-related conditions, such as inflammatory-related reactions,effects and responses, and/or attenuating oxidative stress in anindividual.

BACKGROUND TECHNOLOGY

Lipid peroxidation products are early stage and major mediators in theinflammatory cascade. These products include endogenous and/or exogenousaldehydes, such as 4-hydroxy-nonenal, malondialdehyde and acrolein andact by stable modification of proteins, which subsequently alter theirstability and functionality upon adduct formation. Several diseases havebeen shown to be associated with or caused by enhanced adduct formationwith aldehydes, including neurodegenerative diseases (Alzheimer,Parkinson), atherosclerosis, osteoarthritis, cataract etc.

Aldehyde and keto groups are reactive electrophiles. They will reactwith nucleophiles, preferentially nucleophiles containing nitrogenhaving a free electron pair, to form Schiff bases or imine derivatives.Subsequent rearrangement e.g. of the Amadori type, may produce a newaldehyde or keto group susceptible to reaction with yet anothernucleophile. This forms the basis of protein cross-linking andsubsequent denaturation.

Another in vivo aldehyde modification is the reaction of amino groups,e.g. in proteins, with carbohydrates having a reducing end with a maskedaldehyde functionality. This non-enzymatic glycation produces “AdvancedGlycation End products” also called AGE modifications of proteins thatpotentially may lead to inflammation. These reactions are related to theMaillard reaction.

Several molecules, including carnosine hydralazine etc, exhibit aldehydescavenging properties in vitro, by trapping the aldehyde as an imine orSchiff base, but the effects are questionable or sparse when applied invivo and in a clinical setting. The foremost reason for a limitedaldehyde scavenger effect is the small sizes of these molecules whichgive them an unfavourable pharmacokinetic profile.

It is believed that the active principle of the inventive composition iscapable of mitigating the effects an early stage mediator might have onan inflammatory-related response due to its content of reactive groupswhich are capable of forming covalent binding with an electrophiliccarbonyl group and/or an electrophilic carbon-carbon multiple bond. Thecarbonyl group is in particular believed to be an aldehyde group whichpossibly is conjugated with a carbon-carbon multiple bond(α,β-unsaturation). Our results suggest that the favourable effect foundrequires the factual formation of covalent binding between our activeprinciple and an early stage mediator via the reactive groups indicated.However, since this hasn't yet been finally confirmed, the invention isfor the time being (at the filing of this specification) not linked tosuch a mechanism. There may still be other explanations for thefavourable and surprising effects we have accomplished with our activeprinciple containing selected carrier-bound reactive nucleophilicgroups.

The invention is concerned with two main kinds of mediators giving raiseto inflammatory-related responses:

-   -   a) Endogenous mediators are formed in the individual where they        exert their effects. This group includes as one subgroup        mediators/substances which are part of a response leading to        inflammation and as a second subgroup mediators/substances which        are capable of causing undesired effects which can be considered        as part of an inflammatory-related response but not necessarily        as inflammation, e.g. discomfort, head-ache, hangover, cataract        etc., and    -   b) Exogenous mediators are formed outside the individual where        they exert their effects.

They are capable of causing an inflammatory-related effect in vivo,and/or have to be transformed in vivo to an endogenous mediator beforesuch an effect can be accomplished.

Inflammatory-related conditions (as well as inflammatory-relatedreactions and effects) will in the context of the invention encompassinflammation as well as the undesired conditions discussed in thepreceding paragraphs if not otherwise indicated.

Illustrative scientific articles and patent documents concerningaldehyde containing mediators and/or scavenging of such mediators are:

-   1. Burcham et al., WO 2003055487 Method of controlling damages    mediated by α,β-unsaturated aldehydes.-   2. Burcham et al., WO 2006002473 Method of controlling damages    mediated by α,β-unsaturated aldehydes.-   3. Cho et al., WO 2009091992 Repairing damaged nervous system tissue    with nanoparticles.-   4. Guitto et al., Synthesis and evaluation of neuroprotective    α,β-unsaturated aldehyde scavenger histidyl-containing analogues of    carnosine. J. Med. Chem. 48 (2005) 6156-6161.-   5. Guitto et al., Malondialdehyde scavenging and aldose-derived    Schiffs bases' transglycosylation properties of synthetic    histidyl-hydrazide carnosine analogs. Bioorg. Med. Chem. 15 (2007)    6158-6163.-   6. Hamann et al., Hydralazine inhibits compression and    acrolein-mediated injuries in ex vivo spinal cord. J. Neurolog    104 (2008) 708-718-   7. Hamann et al., Acrolein scavenging: a potential novel mechanism    of attenuating oxidative stress following spinal cord injury. J.    Neurochem 111 (2009) 1348-1356.-   8. Ito et al., Anti-inflammatory function of an in situ    cross-linkable conjugate hydrogel of hyaluronic acid and    dexamethasone. Biomaterials 28 (2007) 178-1786.-   9. Monnier et al., Wake up and smell the Maillard reaction. Sci.    Aging Knowl. Environ. 50 (2002) pe21-   10. Negre-Salvayre et al., “Review: Advanced lipid peroxidation end    products in oxidative damage to proteins. Potential role in diseases    and therapeutic prospects for the inhibitors. Br. J. Pharmacol.    153 (2008) 6-20-   11. Reddy et al., Carnosine: a versatile antioxidant and    antiglycating agent. Sci. Aging Knowl. Environ. 18 (2005) pe12

The synthesis and use of polymers exhibiting covalently attachedaldehyde-reactive functionalities or aldehyde groups have been describedin WO 2009108100 (IPR-Systems AB) and references cited therein. Thepublication indicates that the hydrogel formed by reaction of these twodifferently functionalized polymers with each other in vivo may behighly biocompatible causing low or no host defence reaction includinglow or no inflammation. Nothing has been concluded about the reason forthis.

OBJECTS

The primary goal with the present invention is to at least partiallyimprove the effect of earlier suggested low molecular weight substancesfor inhibiting mediators of the above-mentioned type, i.e. to improvethe treatment and/or prevention of inflammatory-related effects of themediators. The improvements may be related to

-   -   a) the therapeutic effect when treating and/or preventing        inflammation and/or other inflammatory-related conditions,    -   b) the versatility of the use of agents mitigating undesired        effects of endogenous and/or exogenous inflammatory-related        mediators,    -   c) the pharmacokinetics of the active principle in order to        accomplish a higher and/or prolonged effect, etc.

INVENTION

The present inventors have recognized that immobilization of relevantscavenger functionalities to a macromolecular carrier would improve theeffects of the corresponding low molecular weight scavenger molecule.Unexpectedly it has been found that the optimal functionalities havebeen found amongst reactive groups that normally are used forcross-linking macromolecular carriers and/or for the synthesis ofcarrier-bound therapeutic active entities (WO 2009108100 and referencescited therein).

In the present specification our principle is demonstrated by thesynthesis of functionalized carriers which are capable of aldehydescavenging. In the experimental part this kind of construct is shown toinhibit oxidation of human albumin by acrolein in a dose-dependentmanner in vitro (example 1). Further, the in vivo effect on inflammationis demonstrated both in rodents and humans using a wound healing model(example 2 and 3). The effect on lowering inflammatory-related mediatorsin tobacco smoke is also demonstrated (example 4).

First Main Aspect (Composition)

The first aspect is a composition for treating or preventinginflammatory-related conditions in an individual suffering from or beingat risk for suffering from such conditions. The main characteristicfeature is that the composition comprises as an active principle (=AP) acarrier which exhibits a plurality of a scavenger structure which whenpresent on the carrier is capable of mitigating and/or neutralising theactivity of a mediator of inflammatory-related conditions.

Second Main Aspect (Method)

The second main aspect of the invention a method for treating orpreventing inflammatory-related conditions in an individual sufferingfrom or being at risk for such conditions. The main characteristicfeature of the method comprises the steps of:

-   -   i) providing a composition containing as an active principle        (=AP) a carrier which exhibits a plurality of a scavenger        structure which is capable of mitigating and/or neutralising the        activity of a mediator of inflammatory-related conditions, and    -   ii) contacting AP with said mediator a) within said individual,        or b) separate from said individual.

Alternative (a) means that the composition containing AP is administeredto said individual.

The individual is typical an animal, such as a vertebrate, withparticular emphasis of a mammal such as a human being. In the case themethod is a therapeutic treatment the individual is typically a patient.

The mediator may be water-soluble or water-insoluble. The mediator istypically of the same kind as mediators participating in an early stageof inflammatory-related conditions (=early stage mediator) and is assuch typically of a low molecular weight, such as ≦3000 dalton or ≦2000dalton or ≦1000 dalton or ≦500 dalton. This does not exclude that thereare mediators of molecular weights ≧3000, e.g. exhibiting biopolymericstructure, such as protein/polypeptide structure and/or carbohydratestructure and/or nucleic acid structure.

Step (ii) means that the inflammatory-related effects caused by amediator is mitigated by neutralization of the mediator.

Step (ii.a) means that the contacting and neutralization of the mediatoris taken place in vivo, i.e. within the body, on the skin etc of theindividual suffering from or being at risk for inflammatory-relatedconditions involving the mediator

Step (ii.b) encompasses two main situations:

-   -   A) The mediator is present in a fluid, tissue, organ etc, which        originates from an individual. The fluid, tissue, organ etc is        after neutralization of the mediator delivered to an individual        suffering from or being at risk for inflammatory-related        conditions, i.e. the contacting and the neutralization of the        effect of the mediator are taking place ex vivo and/or        extracorporeal. The mediator is primarily endogenous but may        also be exogenous. The individual receiving the treated fluid,        tissue, organ etc may be the individual from which the fluid,        tissue, organ etc originates, or some other individual.    -   B) The mediator is present in a fluid, which does not originate        from an individual, e.g. ambient atmosphere, gas to be inhaled,        water etc and typically has a non-biological origin. The fluid        is after the neutralization of the mediator allowed to be in        contact with the individual suffering from or being at risk for        inflammatory-related conditions, i.e. the contacting and the        neutralisation of the effect of the mediator are taking place in        vitro and external to the individual suffering from or being at        risk for inflammatory-related conditions. The mediator is        typically exogenous and the neutralization is taking place        before the mediator is brought into contact with the individual        suffering from or being at risk for inflammatory-related        conditions. Typical routes for bringing the fluid in contact        with the individual after neutralization of the mediator are        inhaling, oral, dermal etc.

The Composition

The composition may contain one or more formulations where at least oneof them comprises AP or reagents necessary for the formation in vivo ofAP (e.g. as described in WO 2009108100 for compositions used forformation in vivo of extracellular matrices).

The Active Principle (=AP)

AP comprises a carrier exhibiting the plurality of the scavengerstructure. Every scavenger structure is firmly attached to the carrier,for instance covalently. AP as well as the carrier as such may besoluble or insoluble in aqueous liquids such as water, body fluids, suchas blood, serum, plasma, urine, lymph, lachrymal fluid, intestinaljuice, gastric juice, saliva, synovial fluid etc.

AP may be fixed to a water-insoluble support that may be of variousphysical and/or geometric appearances depending on the intended use. Seefurther below.

Either one or both of the carrier and the support should be inert in thesense that they should not participate as competing reactants in thereaction between the scavenger structure and the mediator. Both of themshould have an acceptable biocompatibility causing low or no hostdefence reactions including low or no inflammation.

The Scavenger Structure

The scavenger structure when present on the carrier mitigates and/orneutralizes the activity of the mediator. The mitigation/neutralizationmay be irreversible or reversible with preference for the former. It cantake place by capturing the mediator to the carrier or by leaving themediator in (=transforming the mediator to) an inactivated form which isunbound to the carrier. When capturing is at hand, the scavengerstructures and reactive groups on the mediator typically react with eachother leading to the formation of covalent bonding which attaches themediator in a transformed and neutralised form to the carrier (=adductformation).

The scavenger structure comprises a first nucleophilic centre whichpreferably is capable of participating in an addition reaction with thecarbonyl group (C═O) of an aldehyde group,—and/or with a C,C-multiplebond to which one or more electron-withdrawing substituents preferablyare directly attached. Reactive species of this kind occurring in vivoand suggested to be involved in undesired inflammatory-related effectsare for instance malondialdehyde, sugar aldehydes, α,β-unsaturatedaldehydes —CH═CH—CH═O, such as acrolein, 4-hydroxy-non-2-enal etc(examples of early stage inflammatory-related mediators).

The nucleophilic centre (first centre) of the scavenger structurepreferably comprises a single-bonded first heteroatom N, O or S (═X¹)which exhibits

-   -   a) a free electron pair,    -   b) one or two hydrogens, and    -   c) one or two organic groups R′— (monovalent) and —R″—        (divalent) directly bound to the heteroatom.

The preferred heteroatoms are N and S. S is preferably combined with thepresence of a second nucleophilic centre, such as a primary or secondaryamino, in the same scavenger structure as discussed below. The bivalentorganic group —R″— provides binding to the carrier via one of its freevalencies. The other free valency of —R″— as well as the free valency ofthe other organic group R′— are directly attached to the heteroatom X¹.

Generically a nucleophilic centre has the formula:X¹(—R″—)(—R′)_(m)H_(n)  (formula I)where X¹, R′— and —R″— are as defined in the preceding paragraph and mis 0 or 1 and n is 1 or 2 with the sum of m plus n being 2 for X¹═N and1 for X¹═S and O.

A single-bonded atom means that the atom is directly bound to otheratoms only by single bonds. A multiple-bonded atom means that the atomis directly bound to another atom by a triple or a double bond. Theatoms referred to are primarily N, O, S and carbon.

The preferred nucleophilic centres are typically uncharged wheninteracting with the mediator. For a nucleophilic centre which is anuncharged base or acid form of an acid-base pair ≧5%, such as ≧25% or≧50 or ≧75%, of the total concentration of the acid-base pair should bein uncharged form.

When the heteroatom X¹ is N, the ability to react with an aldehyde groupwill include that the adduct formed is capable of undergoing spontaneouselimination of water (H₂O) to the formation of an imine structure(—CH═NR″—, m=0 and n=2) and/or an enamine structure (—CH═CHNHR″—, m=0and n=2) or —CH═CHNR′R″—, m=1 and n=1) with both alternatives requiringa hydrogen (α-hydrogen) on a sp³-hydridised α-carbon of the aldehydegroup —CHO). When the heteroatom X¹ is S or O, m=0 and n=1 which meansthat the structure obtained upon elimination of H₂O is thioenolate orenolate (—CH═CHX¹R′) (provided there is an α-hydrogen of the aldehydegroup —CHO). These elimination reactions typically mean formation of amore stable product and/or a product that may react further to a furtherstabilized “end”-product. The selection of scavenger structurescontaining groups permitting subsequent reactions which end up instabilized end products will support irreversibility of the initialaddition reaction, and are as a rule preferred.

The reaction of the first nucleophilic centre and a reactiveC,C-multiple bond on a mediator will result in a primary adduct whichcomprises the structure >CH—CHX¹— (for C,C-double bonds) and if themultiple bond is α,β to an aldehyde group there can be formed differenttautomeric adducts. e.g. —CHX¹—CH═CHOH (enol) and —CHX¹—CH₂—CH↑O (keto)which will enable another nucleophilic centre of the same or anotherscavenger structure to react with the mediator molecule ending up instabilized end products.

Either one or both of the organic groups R′— and —R″— comprise astructure of the formula—CH₂(X⁴)_(o′)(C═X³)_(n′)(X²)_(m′)—  (formula II)where

-   -   a) each of m′, n′ and o′ is 0 or 1, with preference for m′ being        1 with further preference for either one or both of n′ and o′        also being 1,    -   b) each of X², X³, and X⁴, is selected amongst NH and a        heteroatom S or O, with preference for either one or both of X²        and X⁴ being selected amongst NH and O with further preference        for X³ being selected amongst NH, O and S,    -   c) the left free valence provides binding to a monovalent alkyl        group R*— or to the carrier via at least a bivalent alkylene        group —R**—, each of which comprises the methylene group —CH₂—        shown of formula II,    -   d) the right free valency binds directly to the first heteroatom        X¹.

The substructure C═X³ (═B) includes also other ester- and amide-formingsubstructures which derive from acid functions and form an esterfunction when X² and/or X⁴ are oxygen and/or an amide function when X²and/or X⁴ are NH, e.g. sulphonamide (B is S(═O)₂) or phosphone amide (Bis P═O(NH₂) or P═O(OH), n′=1).

Either one or both of the monovalent alkyl group R*— and the bivalentalkylene —R**— may be straight, branched or cyclic and possibly containone or more structures selected amongst ethers (—O—, —S—), hydroxy(—OH), mercapto (—SH) and amino (—NH—, —NH₂). Each free valencesrepresent binding to sp³-hybridised carbon (=alkyl carbon). Either oneor both of these alkyl groups are preferably a lower alkyl which in thiscontext means that they comprise one, two, three, four, five up to tensp³-hybridised carbons typically with at most one heteroatom O, N and Sbound to one and the same carbon. The groups are typically inert in thesense that they are not participating in the reaction which neutralisesthe mediator. The hydrogens given in formula (I) and/or itssubstructures may be replaced with an alkyl group selected amongst thesame alkyl groups as discussed for R*—.

It is preferred that the bivalent group —R″— which attaches the firstnucleophilic centre to the carrier comprises a substructure complyingwith formula I and/or II.

The structural elements (substructures) discussed in the precedingparagraphs will support delocalisation of electrons and thereforefurther support irreversibility of the initial addition reaction.

Preferred scavenger structures thus have a nucleophilic centre whichcontain the first heteroatom X¹ together with a structure complying withformula II and are selected amongst:

-   -   a) amino groups preferably primary or secondary amino groups    -   b) hydrazide groups such as —NH—NH₂, e.g. as part of a —CONHNH₂        group, a semicarbazide group such as —NHCONHNH₂, a carbazate        group such as —OCONHNH₂, a thiosemicarbazide group such as        —NHCSNHNH₂, a thiocarbazate group such as —OCSNHNH₂ (formation        of hydrazone, semicarbazone, thiocarbazone linkages/groups etc        when undergoing addition/elimination reactions with an aldehyde        group)    -   c) aminooxy groups, such as —ONH₂ etc (formation oxime        linkages/groups etc when undergoing addition/elimination        reactions with an aldehyde group),    -   d) a thiol group e.g. —SH (Michael addition products are formed        when the thiol group reacts with a C,C-double bond. The product        may undergo keto-enol tautomerisation when the double bond is        α,β to a keto- or aldehyde-carbonyl, see above).

The free valence indicated in each of the groups given in the precedingparagraph preferably attaches the nucleophilic centre to the carrier viaa linker structure comprising the above-mentioned bivalent alkylenegroup —R**—. A hydrogen bound directly to nitrogen may be replaced witha monovalent alkyl group selected amongst the same alkyl groups as R*—as long as they are not substantially counteracting the desiredreactivity of the unsubstituted form of the nucleophilic centre. Thusthe hydrogen in a thiol group and in a hydroxyl group can not bereplaced, for instance. Two replacing alkyl groups may form a cyclicstructure together with atom to which they are attached, i.e. form abivalent alkylene group e.g. selected amongst the alternatives for the—R**— group.

The bivalent structures —R**— and —R″— discussed above comprises next tothe carrier a linker structure which does not negatively affect thedesired effect of the nucleophilic centre of the scavenger structure.Such structures are not part of the invention and suitable suchstructures can be designed by the average-skilled person in the field.

In certain preferred scavenger structures there may be a secondnucleophilic centre which a) may be part of one of the organic groups,e.g. the R*— or the —R**— group, and b) contain a first heteroatom N, Oor S (═Y¹) in the same manner as for the first nucleophilic centre. Inprinciple this means that this second nucleophilic centre complies withthe formula:Y¹(—R″—)(—R′)_(m)H_(n)  (formula III)and the formula—CH₂(Y⁴)_(o″)(C═Y³)_(n″)(Y²)_(m″)  (formula IV)where m, n, m″, n″, o″, Y¹, Y², Y³, Y⁴, —R″— and —R′ are selected in thesame groups of variables as m, n, m′, n′, o′, X¹, X², X³, X⁴, —R″— and—R′ of formula I and II. This includes that hydrogens (H) may bereplaced as suggested for formulae I and II.

The heteroatom Y¹ preferably is part of

-   -   a) an —NH₂ group where the free valence preferably may bind to a        sp³-hybridised carbon, or    -   b) a thiol group —SH where the free valence preferably may bind        to a sp³-hybridised carbon.

Each of m″, n″ and o″ in formula IV is 0 in both (a) and (b).

The distance between the first heteroatom Y¹ and the first heteroatom X¹is typically larger than two or three atoms with upper limits being e.g.20 atoms with preference for 4, 5 or 6 atoms between these twoheteroatoms. The distance should support intra-molecular cyclisation,typically via one or more addition reactions. This cyclisation typicallycomprises an addition reaction between the second nucleophilic centreand

-   -   a) a carbon-carbon or a carbon-heteroatom double bond formed as        described above by reaction of the first nucleophilic centre        with the starting aldehyde group, and/or    -   b) a reactive multiple C,C-bond present already in the starting        aldehyde, such as a reactive double C,C-bond, e.g. α,β to the        aldehyde group, and/or    -   c) a second keto or aldehyde carbonyl group provided such a        group is present in the mediator molecule.

The result of the cyclisation is an n-membered ring-structure containingthe first heteroatom Y¹ and the first heteroatom X¹ with n in n-memberedbeing an integer ≧3 with preference for 5 or 6. Larger rings may also beformed, such as 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-membered rings, aslong as steric considerations and relative positions of functionalgroups so admit. The cyclisation may be followed by rearrangementreactions, e.g. intramolecularly, and/or elimination reactions creatingcarbon-heteroatom double bond(s), ring-openings etc.

The Carrier

The selection of suitable carriers depends on the requirements of aparticular use. The typical carrier is selected amongst macromolecularcompounds, i.e. is a compound which has a molecular weight of ≧2000dalton, preferably ≧10000 dalton or ≧50000 dalton, and preferablyexhibits a polymeric structure, i.e. is a polymer which may be ahomopolymer, copolymer or a chemical adduct between two or more polymersof different polymeric structure. Other suitable carriers may havemolecular weights ≦2000 dalton and exhibit polymeric structure asindicated by the possibility of the low numbers of monomeric unitsdiscussed below, e.g. ≧20 and ≦100. The term “adduct polymer” in thiscontext means a product formed by reacting two polymers exhibitingmutually reactive groups capable of forming covalent bonds that link thetwo polymers together upon reaction of the two mutually reactive groupswith each other. See for instance WO 2009108100 (IPR-Systems AB) andreferences cited therein. Suitable macromolecular carriers may thus beselected amongst synthetic polymers (=man-made polymers), biopolymers(nature-made polymers such as polysaccharides, polypeptides, proteinsetc) and biosynthetic polymers where “biosynthetic polymer” refers to amacromolecular carrier or compound exhibiting both a synthetic polymericstructure and a biopolymeric structure. A carrier polymer may becross-linked or not cross-linked. With respect to branching the polymermay be unbranched, i.e. linear, or branched including eitherhyperbranched or dendritic. The degree of branching may thus varybetween 0 and 1, such as be ≧0.10 or ≧0.25≧0.5≧0.75 or ≧0.90 and/or≦0.90 or ≦0.75 or ≦0.50 or ≦0.25 or ≦0.10. Cross-linked polymers are asa rule insoluble in aqueous liquids while the solubility ofnon-cross-linked polymers depend on the overall structure of thepolymer, e.g. presence and amount of polar and/or hydrophilic groups.

Carrier polymers may also be derivatized to contain non-polymeric orpolymeric groups, for instance cross-links, substituents, charged oruncharged groups, scavenger structures (as discussed above) etc.Macromolecular carriers which are insoluble in aqueous liquids may havedifferent physical and geometric shapes as discussed for supportmaterials elsewhere in this specification.

The term polymer above includes organic as well as inorganic polymers.

The macromolecule or polymer used in the carrier may be water-insolubleand suspensible in aqueous liquid media (when in particle form).

Polymers and other macromolecules suitable as carrier material may behydrophilic or hydrophobic with preference for hydrophilic. Pronouncedhydrophobic macromolecular carriers are as a rule insoluble in aqueousliquids meaning that there may be a risk for host defence reactions withthem and also that the availability of nucleophilic centres for reactionwith inflammatory-related mediators may not be optimal. In order toovercome this kind of problems, it is often preferred to introducehydrophilic groups on their surfaces (hydrophilization). Theintroduction of hydrophilic groups may among others be accomplished by

-   -   a) coating with a hydrophilic material,    -   b) selecting building blocks/monomers which exhibit hydrophilic        groups and appropriate conditions during synthesis of the        macromolecular compound, and    -   c) chemical derivatisation with hydrophilic groups subsequent to        the synthesis of the basic hydrophobic polymer etc.

The hydrophilicity of a group, structure or carrier molecule increasesas a rule with an increase in the ratio r=the sum of the number ofheteroatoms O, N and S divided by the sum of the number of carbon atoms.Hydrophilic groups/compounds typically have an r≧0.5, preferably ≧1.0,and for hydrophobic groups r<1.0, preferably ≦0.5. Typical hydrophilicgroups are hydroxy, amino, amido, carboxy (including free acid carboxylas well as carboxylate (ester ester and salt) etc. Typical hydrophobicgroups are alkyls (C_(n)H_((2n+1))—, C_(n)H_((2n−1))—, C_(n)H_((2n−3))—etc), phenyls including alkyl phenyls, benzyl including otherphenylalkyls etc. A carrier macromolecule typically comprises a polymerbackbone which comprises ≧5, or more preferably ≧10 such as ≧25different and/or identical monomeric units linked together. The polymermay carry projecting or pending polymeric and/or non-polymeric groups ofvarious lengths and kinds. A carrier polymer is preferably hydrophilicwith hydrophilic groups selected amongst those given elsewhere in thisspecification. The most preferred hydrophilic group is hydroxy with thepreferred carrier polymers and/or other macromolecular carrier beingselected by poly hydroxy polymers (PHP or PH-polymers) exhibiting ≧5,with preference for ≧10, such as ≧25 or ≧50 hydroxyl groups and/or ≧5monomeric subunits each of which exhibits one, two, three, four or morehydroxyl groups per unit.

Typical polymers that may be present in polymeric carriers are a)polyester polymers, b) polyamide polymers, c) polyether polymers, d)polyvinyl polymers, e) polysaccharides etc. A carrier may comprise oneor more of these polymers/polymeric structures.

Polyester polymers are in particular obtained by polymerisation of a)monomers exhibiting at least one hydroxy group and at least one carboxygroup, or b) a mixture containing monomers exhibiting two or morehydroxy groups and monomers exhibiting two or more carboxy group.

Polyamide polymers are in particular obtained by polymerisation of a)monomers exhibiting at least one amino group and at least one carboxygroup, or b) a mixture containing monomers exhibiting two or more aminogroups and monomers exhibiting two or more carboxy group.

An important group of polyamides are those that exhibit polypeptidestructure together with a plurality of hydroxy groups (PH-polymers).Suitable polyamide polymers of this kind are typically based onhydroxy-,amino-carboxylic acids as monomers, in particular with theamino group positioned a to the carboxylic group, e.g. serine,threonine, tyrosine, proline etc.

Polyether polymers are typically used in combination with otherpolymeric structures, e.g. polymers of (a), (b), (d) and/or (e) above,which are polyfunctional with respect to the presence of groups such ashydroxy, amino etc. Typical polyether polymers are polyethylene oxideand various copolymerisates between ethylene oxide and other loweralkylene oxides, lower epihalohydrins etc.

Polyvinyl polymers which may be suitable as polymeric carriers in theinvention are typically found amongst polymers containing one, two ormore different monomeric units selected amongst hydroxyalkyl acrylatesand methacrylates, N-hydroxyalkyl acryl- and N-hydroxyalkylmethacrylamides, hydroxyalkyl vinyl ethers, vinyl esters etc. Polyvinylalcohols are typically obtained by partial hydrolysis of polyvinylesters meaning that polyvinyl alcohols that are preferred in theinvention typically exhibit residual amounts of ester groups (≦10% or≦5%).

Typical polysaccharides that may be present in carriers used in theinvention include dextran, starch, agarose, agaropektin, cellulose,glucosamino glucanes (GAG), and derivates of these polysaccharides etc.The most interesting polysaccharides are dextran, certain glucosaminoglucanes (GAG) such as hyaluronic acid etc.

A polymer to be used in the carrier may have been derivatized, e.g.cross-linked and/or functionalized after its synthesis.

The scavenger structure including the first, the optional secondnucleophilic centre and the various heteroatoms discussed for thescavenger structures are typically part of one and the same organicgroup/substituent attached to the macromolecular carrier. In certainvariants different parts of a scavenger structure may be part ofdifferent groups/substituents attached to the carrier and/or part of thecarrier.

Sizes/molecular weights of suitable carrier polymers will among othersdepend on the actual application/use of the composition/method of theinvention. Thus suitable polymeric carriers with respect to a particularpolymeric structure and/or size may vary within a wide interval. Thus asa rule the number of monomeric subunits (mean value) of a polymerpresent in the carrier may be ≧20 or ≧100 or ≧200 or ≧300 or ≧500 or≧1000 or ≧2000 or ≧20 000 or ≧50 000 and/or ≦50 000 or ≦20 000 or ≦2000or ≦1000 or ≦500 or ≦300 or ≦200, or ≦100 (with the proviso that ≧-limitalways is lower than a ≦-limit when these values are combined to defineintervals). Preferred numbers of monomeric units may in some cases befound in the interval of 200-600 which in particular applies to thepolyvinylalcohol used in the experimental part.

Suitable numbers of scavenger structures or nucleophilic centres permonomeric unit of a polymer of the carrier will also depend on the use,the scavenger structure, the mediator etc and may thus be found within awide interval, such as ≦80%, such as ≦50% or ≦20% with typical lowerlimits being 0.01% or 0.1% or 1% where 100% corresponds to one scavengerstructure or nucleophilic centre per monomeric unit. For scavengerstructures containing two or more nucleophilic centres the number ofnucleophilic centres per monomeric unit may exceed 100%, such as ≧100%or ≧125% or ≧150%.

Other Features of the Composition

AP is present in the composition as an AP-formulation in which AP is:

-   -   a) in dry form, for instance as free particles,    -   b) in dissolved form, typically in an aqueous liquid medium, and    -   c) in suspended/dispersed form, i.e. as water-insoluble        particles suspended in an aqueous liquid medium,    -   d) attached to a support which is insoluble in aqueous liquid        media.

The term “dissolved” in this context means that AP is present as asolute. AP particles comprise AP in a pure form or diluted with somesolid material. Useful concentrations of AP in formulations according to(b) can be found within a broad interval. For liquid formulations e.g.within the interval of 0.1 μg-100 mg/mL.

The composition may in addition to AP contain buffers, salts etcrequired for enabling acceptable conditions in vivo for the patient andfor the reaction of AP with an inflammatory-related mediator to occur.These constituents may be co-formulated with AP in the AP-formulation.

A potentially important variant of the inventive composition comprisesformulations enabling production of cross-linked carrier polymersexhibiting a plurality of a nucleophilic structure that can be used as ascavenger structure (WO 2009108100, IPR-systems AB and references citedtherein). The cross-linking may take place in vivo or ex vivo. In thisvariant the AP-formulation of the inventive composition is representedby at least two subformulations:

-   -   1) a first subformulation containing a macromolecular carrier        exhibiting a plurality of a reactive nucleophilic group which        has the potential of acting as a scavenger structure for an        inflammatory-related mediator of the kinds discussed above, and    -   2) a second subformulation containing a cross-linking reagent,        preferably in the form of a polymer, and exhibiting (comprising)        a plurality of a reactive electrophilic group which is capable        of reacting in aqueous media with the reactive nucleophilic        group of the macromolecular carrier to the introduction of        covalent cross-links in the macromolecular carrier.

The macromolecular carrier in the first subformulation may be selectedamongst the macromolecular carriers discussed above. When thecross-linking reagent in the second subformulaion is a polymer thispolymer may be selected amongst the polymeric macromolecular carriersdiscussed above.

The cross-linked carrier obtained by mixing the first subformulationwith the second subformulation will contain a plurality of scavengerstructures if the reactive nucleophilic group at the time of mixing isin molar excess compared to the reactive electrophilic group. Molarexcess in this context typical means excess with a factor ≧2, such as ≧5or ≧10 or ≧20. If the starting carrier and the cross-linking reagent isproperly selected the obtained product will form a hydrogel in situ.

It can be envisaged that this kind of two-component compositions may beadvantageous when administering by injection highly viscous solutions ofhigh-molecular weight hyaluronic acid (desired polymer). Highly viscoussolutions of hyaluronic acids are difficult to inject and administrationof hyaluronic acid is often linked to a risk for adverse effects due toinflammatory-related reactions. These problems are likely to be reducedby injecting at the same location of a patient a composition comprising:

-   -   a) a first subformulation in which the macromolecular carrier is        a low-molecular weight variant of hyaluronic acid in dissolved        form (=a variant having a lower Mw than the Mw of the desired        hyaluronic acid), and    -   b) a second subformulation in which the cross-linking reagent is        also a low-molecular weight variant of hyaluronic acid in        dissolved form,        with the proviso that    -   i) that the reactive nucleophilic group in the first        subformulation is in excess compared to reactive electrophilic        groups in the second subformulation, and    -   ii) that the degree of substitution with respect to reactive        electrophilic groups on the hyaluronic acid of the second        subformulation (cross-linking reagent) is sufficiently low for        producing a carrier in dissolved form, i.e. non-gel form, when        the two subformulations are mixed with each other upon        injection.

The mixing leads to a reaction between the reactive nucleophilic groupand the reactive electrophilic group to the formation of a covalentcross-linking structure. Experimental testing is required for findingoptimal degrees of substitution with respect to the reactiveelectrophilic group in the second subformulation relative to otherreaction variables in order to obtain a carrier product in dissolvedform, i.e. non-gel form.

The injection of the subformulations is preferably done in parallel, forinstance with mixing of the formulations in the used syringe during orjust before the injection is started. The techniques for this kind ofinjections and syringes to be used are well-known in the field; see forinstance WO 2009108100 (IPR-Systems AB).

Synthesis of the Active Principle

AP may be synthesized according to well-known protocols, for instance ofthe kinds given in WO 2009108100 (IPR-Systems AB) and references citedtherein.

Water-Insoluble Support

As mentioned above AP may be fixed to a water-insoluble support. Thissupport material may be selected amongst support materials that have atleast one or more of the following characteristics: a) in the form ofparticles, b) porous or non-porous particles or monoliths allowing ornot allowing, respectively, aqueous liquids and/or inflammatory-relatedmediators to be neutralized to penetrate the support, c) rigid, d) soft,e) elastic, f) compressible, g) gellable (in particular to form ahydrogel when placed in contact with water) etc. The support maycomprise plastics, glass, mineral, metal etc. When the carrier of AP isinsoluble in aqueous media the carrier as such may define its own solidsupport.

Supports may be designed as devices to be used in vivo and/or separatefrom an individual suffering from or being at risk for theinflammatory-related conditions to be treated or prevented. Typicaldevices are implants having AP exposed on their surface, e.g. stents,vascular prosthesis, nets, teeth, bones, joints etc, patches, surgicaldressings, plasters, filters, sutures, contrast media in the form ofparticles etc. This also includes filter and adsorbent material for a)removing the activity of inflammatory-related mediators and/or otherfunctionally similar environmental irritants from non-biological fluidsthat are or will be brought in contact with animals including humansand/or b) ex vivo use, e.g. comprising removal of inflammatory-relatedmediators from biological fluids which derive from an individual andsubsequently are to be returned to an individual suffering from or beingat risk for inflammatory-related conditions. Typical examples ofnon-biological fluids to be treated according to (a) are air containingsmoke, e.g. tobacco smoke, and industrial off-gases. Typical examples ofbiological fluids to be treated according (b) are blood, serum, plasmaetc.

Suitable supports typically comprise polymeric materials, e.g.comprising one or more polymer selected from the same polymers as thecarrier polymers are selected. Typical carrier polymers arepolysaccharides, e.g. cellulose, cross-linked dextran, agarose such ascross-linked agarose etc, polyester polymers e.g. lactic acid copolymerssuch as polyglactin, polyethylenes etc. Other kinds of support materialmay also be used, e.g. ceramic materials, plastics, mineral materials,metals, composite material, activated carbon etc. Porous forms of thesesmaterials may be used as filters and/or adsorbent material.

Attachment to the support may be accomplished by mixing, coating,impregnating etc the support with AP according to techniques known inthe field. Alternatively, the macromolecular carrier of AP may be partof the material from which a support/device is made.

Contacting AP with an Inflammatory-Related Mediator (Step (ii) of theMethod)

As discussed above the contacting of AP with the mediator may take placein vivo of or separate from the individual to be treated.

The amount of AP in the composition which is brought into contact withthe mediator is effective in the sense that the inflammatory-relatedresponse to be treated is mitigated and/or neutralised to an acceptablelevel. The suitable dosage (per administration) for in-vivo applicationsdepends on the particular medical indication, formulation (e.g. kind of,support material, AP, scavenger structure, concentrations etc) etc andthus is selected within a broad interval, e.g. 10⁻¹²-10² g with10⁻⁶-10⁻³ g as particularly interesting interval. Experimental testingis needed for individual cases.

Contacting in vivo comprises administration of the inventive compositionsystemically or locally depending on the particular medical indicationtreated and/or formulation used. Local administrations such as topical,dermal, nasal, intra-vitreal, intra-articular, oral, rectal,intra-osseous etc are typically used when the condition to be treated islocalised to the area of administration or at a location reachable forAP from this area. Systemic administrations such as parenteraladministration, e.g. intravenous and subcutaneous administration orenteral administration, e.g. oral administration etc, are mainly usedwhen the conditions to be treated are occurring at locations not easilyreachable by local administrations. Compare the discussion below ondifferent medical indications.

Medical Indications in which it May be of Interest to Apply the PresentInvention are:

1. Prevention of adherence due to evoked inflammatory reaction duringsurgery or caused by inflammatory diseases, e.g. intestinal adherenceevoked by abdominal surgery or intestinal inflammation, tendon adherenceetc. AP may be delivered locally, for example in the abdominal cavity atthe time of surgery.

Formulation: Solution, dispersion, gel possibly in situ formed hydrogeletc.

Administration: Locally with a syringe or spray device.

2. Spinal cord injury. AP may be administrated systemically or locally,preferably at an early stage within hours after the trauma thushindering oxidative stress and reduction of secondary injury processes.

Formulation: Solution, dispersion, gel possibly in situ formed hydrogeletc.

Administration: Locally at the site of injury, systemically byparenteral intravenous infusion or infusion into cerebrospinal fluid.

3. Burn injury and other large trauma. These conditions are known todramatically enhance the systemic oxidative stress to the patients. Thesystemic delivery of AP may be beneficial to improve recovery anddiminish secondary injury processes.

Formulation: Solution, dispersion etc.

Administration: Systemically, preferably by parenteral intravenousinfusion.

4. Reperfusion injury involves inflammatory mediators including lipidperoxidation products which severely affect tissues and recovery.Reperfusion injury plays a role for example in stroke and brain traumabut also in cardiac arrest. The administration of AP may help to reducereperfusion injury.

Formulation: Solution, dispersion etc.

Administration: Preferably by systemic parenteral intravenous orinfusion into cerebrospinal fluid.

5. Aging. This process affects all living animals including humans. Thebalance between oxidative stress and the biological defence againstoxidative stress is progressively disrupted by aging leading toaccumulation of oxidized proteins and nucleic acids. Systemic deliveryof AP could potentially restore this balance partially by loweringoxidative stress and slow down senescence.

Formulation: Solution, dispersion tablets etc.

Administration: Systemic, preferably by peroral administration but alsoparenteral.

6. Neurodegenerative diseases, e.g. Alzheimer and Parkinsons diseases.Growing evidences show a correlation between neuronal degeneration andoxidative stress including enhanced lipid peroxidation end products andthe deposition of insolvable plaques in the brain. The disruption ofthis cascade by systemic delivery of AP may prevent the development ofneourodegenerative diseases.

Formulation: Solution, dispersion tablets etc.

Administration: Preferably by systemic peroral or parenteral intravenousor infusion into the cerebrospinal fluid.

7. Oxidative stress and inflammation in blood vessels. This is known tocause endothelial dysfunction and atherosclerosis which may be preventedor treated by AP of the invention administered systemically.

Formulation: Solution, dispersion tablets etc.

Administration: Preferably by peroral or parenteral intravenousinfusion.

8. Osteoarthritis-rheumatic disorders-localized cartilage defects. Lipidperoxidation products play an essential role in the development ofdamaged cartilage or lack of cartilage regeneration. The systemic orlocal delivery of AP into affected joints may help restore cartilage orstop cartilage degradation by interrupting oxidative stress to thejoint.

Formulation: Solution, dispersion, hydrogel etc.

Administration: Typically local intra-articular injection or systemicperoral or parenteral administration.

9. Asthma and chronic obstructive pulmonary disease (COPD). These arecommon diseases characterized by inflammation in the lungs. Oxidativestress, including lipid peroxidation products, induces the production ofpro-inflammatory molecules. The local administration by inhalation of APmay diminish the inflammation in the lungs.

Formulation: Solution, dispersions, particles etc

Administration: Typically by inhalation or parentral or peroralsystemic.

10. Severe alcohol intake is associated with hang over. The alcoholmetabolite acetaldehyde and its concentration are highest at the time ofhang-over. The blocking of acetaldehyde via systemic administration ofAP may therefore diminish the symptoms associated with hang over.

Formulation: Solution, dispersion, syrup, tablet, capsules etc

Administration: Systemic peroral or parenteral.

11. Pain including headache and migraine associated with environmentalirritants, e.g. tobacco smoking. Lipid peroxidation products, includingacrolein, from tobacco smoke or other environmental irritants may evokepain. For example, acrolein may induce the release of calcitoninegene-related protein (CGRP) via a specific receptor TRP 1. CGRP mediatesneurogenic inflammation and meningeal vasodilatation associated withheadache and migraine. AP administrated locally in oral and nasal mucosamay prevent or treat the pain.

Formulation: Solution, dispersion, particles etc as nasal or oral spray,nasal drops, mouth rinse liquid etc

Administration: Local delivery or systemic peroral or parenteral.

12. Cataract is characterized by age-related accumulation of oxidizedproteins in the lens which may be prevented by local AP administration,e.g. eye drops.

Formulation: solutions, dispersion, particles etc.

Administration: Intravitreal or by eye drops.

13. Dry eyes are associated with local oxidative stress and the amountsof products of oxidative reactions is increased in tear fluids inaffected patients. Administration of AP may be beneficial in thetreatment or prevention of the disease. AP may also be beneficial forthe treatment of general eye discomfort, e.g. pain and irritation due toallergic or inflammatory reaction in the conjunctiva and/or cornea andafter eye surgery.

Formulation: Solutions, hydrogel

Administration: Locally as eye drops or gel.

14. Peritoneal dialysis is effective in the treatment of renal failure.After some years peritoneal dialysis often becomes less effective due toprogressive ultrafiltration failure. The consequences of oxidativestress from dialysis solution may be prevented by using AP added to thedialysis solution which may diminish structural changes in theperitoneal barrier with less fibrosis.

Formulation: Solution, dispersion, dispersible particles

Administration: As part of the dialysis solution

15. Inflammatory bowel disease, such as Crohns disease and ulcerativecolitis. These diseases may potentially be treated by AP, preferably byperoral or rectal administration.

Formulations: Solution, dispersions, tablets, capsules, syrups etc.

Administration: Oral, per rectal or parenteral.

16. Surgical or traumatic skin wound healing and improved scarformation. AP is delivered locally at the site of the wound or incisionby injection.

Formulation: Solution, dispersion, gel possibly in situ formed hydrogeletc.

Administration: Typically local subcutaneous or intracutaneousinjection.

Typical Devices to which the Present Invention can Apply.

1. Implants. Local or systemic inflammatory reaction may be caused byimplants in animals or humans. Incorporation of AP within the implant orcovering the surface of implants with AP could improve biocompatibilityand prevent rejection or other associated complications.

2. AP immobilized on filters used for extracorpeal procedures, e.g.hemodialysis and plasmapheresis, may trap circulating lipid peroxidationproducts thus diminish oxidative stress to the patient.

3. Surgical or traumatic skin wound healing and improved scar formation.AP may be incorporated into surgical device used such as an impregnatedsuture or surgical dressing.

4. Chronic and diabetic skin wounds. These wounds are caused by reducedblood supply to the skin area. Hypoxia is associated with enhancedoxidative stress and the presence of lipid peroxidation end products. APadministrated locally by the use of a functionalized device, e.g.dressing, plaster or particles may reduce oxidative stress and improvehealing and reduce healing time of the wound.

5. Fluids containing environmental irritants. The exposure to acroleinfrom cigarette smoke or other environmental pollutants may cause severelung injury and negative systemic effects in humans. Acrolein couldeffectively be trapped by cigarette filters or breathing filtersdesigned with AP, e.g. functionalized cellulose filter.

EXPERIMENTAL PART Synthesis of Carbazate-Functionalized PolyvinylAlcohol (PVAC)

Polyvinyl alcohol (5 g, 13-23 kDa) was dissolved in dimethyl sulfoxide(100 mL) while stirring for 1 hour at 80° C. under argon gas. Carbonyldiimidazole (10 g) was added and stirring continued at room temperatureover night. Hydrazine hydrate (10 mL) was then added, the reactionstirred over night, and the product collected and purified by repeatedprecipitation in ethanol. The degree of substitution was determinedspectrophotometrically by performing a trinitrobenzene sulfonic acidassay described elsewhere (Stephen L. Snyder and Philip Z. Sobocinski;Analytical Biochemistry 64, 284-288, 1975).

Example 1 The Effect of PVAC on Acrolein-Induced Protein Oxidation wasShown In Vitro

Eighty micrograms of human albumin was treated with 25 μL of 0.2 μMacrolein for 8 hs at 22° C. Protein oxidation involves the introductionof carbonyl groups into protein side chains. These carbonyl groups willreact with 2,4-dinitrophenylhydrazine (DNPH) to give2,4-dinitrophenylhydrazone (DNP-hydrazone) (Oxyblot Protein OxidationDetection Kit, Millipore). The oxidized proteins were separated on 12%polyacrylamide gels, transferred to polyvinylidine diflouride membrane(Hybond-P, GE Health Care) and Western blot was performed using anti-DNPantibodies followed by HRP-labelled secondary antibody and visualized byusing the ECL method. Solutions of PVAC (12.7% degree of substitution)having carbazate concentrations of 1 mM and 10 mM were prepared andmixed with albumin prior adding acrolein to the samples. The blots showdiminished protein oxidations in PVAC treated samples as compared tocontrols and the effect is dose-dependent.

Example 2 The Anti-Inflammatory Effect of PVAC Demonstrated in a RatWound-Healing Model

An inflammatory skin reaction was evoked by surgical full-thickness skinincision and subsequent closure with resorbable polyglactin (4.0 Vicryl,Ethicon). In the experimental group the suture was treated with PVAC(10% degree of substitution of carbazate groups) by incubation in 16.5mg/mL of PVAC in PBS (32 mM carbazate concentration) for 1 hour at roomtemperature and the sutures were air-dried over night. In the controlgroup sutures were either treated in the same manner using 16.5 mg/mL ofnon-modified PVA or left untreated. Inflammatory reactions were grosslyexamined five days after surgery where the wounds closed withPVAC-impregnated sutures had almost no redness or swelling as comparedto controls. The histological picture also demonstrated lessinflammatory cells without giant cells present in the PVAC group at thistime-point, which validates the anti-inflammatory effects of PVAC. Theinhibition of inflammation during wound healing also seems to affectlate scar formation, which was shown after 8 weeks in one animal withalmost invisible scar at the PVAC-treated site.

Example 3

The clinical validation of the anti-inflammatory effects of PVAC wasshown in a human skin wound-healing model. The experiment was performedas described in example 2 with the following exceptions: Theexperimental full-thickness skin incision towards subcutaneous fat was 4cm in length and closed by PVAC treated vicryl 4.0 suturedintracutaneously instead of transcutaneous single sutures. The controlincision was closed by untreated suture. Gross inspection after 1 weekdemonstrated almost no signs of inflammation including swelling andredness at PVAC treated site, whereas in the control the surgicalincision and suture evoked an apparent inflammatory reaction.

Example 4

The effect of PVAC on acrolein-mediated protein modification fromcigarette smoke was demonstrated. PVAC at concentration of 4 mg/mL (10mM) and volume 200 μL was dispersed within filters in filter cigarettes(Marlboro) and allowed to air-dry at room temperature for 4 h. Smokefrom PVAC-treated cigarettes or non-trated controls was subsequentlyair-bubbled into solution of human serum albumin in PBS (4 ug/ml,Sigma-Aldrich). Smoke-treated albumin solutions were subsequentlyanalysed by western blot using mouse anti-acrolein antibody (Abcam,Cambridge, U.K) and HRP-labelled anti-mouse secondary antibody (R&DSystems, Minneapolis, Minn., U.S.A.). The signals were visualized usingthe ECL method. The results show a reduction of acrolein-modifiedalbumin by 30-50% in PVAC-treated group as compared to non-treatedcontrol.

While the invention has been described and pointed out with reference tooperative embodiments thereof, it will be understood by those skilled inthe art that various changes, modifications, substitutions and omissionscan be made without departing from the spirit of the invention. It isintended therefore that the invention embraces those equivalents withinthe scope of the claims which follow.

The invention claimed is:
 1. A composition for treating or preventinginflammatory-related conditions comprising an active principle (=AP)comprising a polyvinyl alcohol carrier which exhibits a plurality of ascavenger structure which is capable of mitigating and/or neutralisingthe activity of a mediator of inflammatory-related conditions, saidscavenger structure comprising carbazate as a nucleophilic centre, saidAP being attached to a support made of a material selected from thegroup consisting plastic, glass, metal, mineral, ceramic and polymericmaterial.
 2. The composition of claim 1, wherein, the scavengerstructure of the polyvinyl alcohol carrier further comprises b) a secondnucleophilic centre which exhibits a single-bonded first heteroatom N, Oor S (═Y¹) and complies with formula IIIY¹(—R″—)(—R′)_(m)H_(n)  (formula III) where: a) Y¹ exhibits a freeelectron pair, b) m is 0 or 1 and n is 1 or 2 with the sum of m plus nbeing 2 for Y¹═N and 1 for Y¹═S and O, c) —R″— is a bivalent organicgroup providing attachment to the carrier via one of its free valencesand direct attachment to the heteroatom Y¹ at the other one of its freevalences, and d) R′— is a monovalent organic group directly attached tothe heteroatom Y¹ via its free valence; and said first heteroatom Y¹ iscapable of participating in an intramolecular addition reaction with amultiple bond formed when the carbazate is reacting with a keto oraldehyde carbon or a reactive multiple bond of an inflammatory relatedmediator.
 3. The composition of claim 1, wherein the support is made ofa polymeric material selected from the group consisting ofpolysaccharides and polyester polymers.
 4. The composition of claim 1,wherein the AP is present in a concentration of 1 μg-100 mg/ml.
 5. Thecomposition of claim 1, wherein the polyvinyl alcohol carrier has200-600 monomeric units.
 6. A composition for treating or preventinginflammatory-related conditions, comprising as an active principle (=AP)a polyvinyl alcohol carrier which exhibits a plurality of a scavengerstructure which is capable of mitigating and/or neutralising theactivity of a mediator of inflammatory-related conditions, saidscavenger structure comprising carbazate as a nucleophilic centre, saidpolyvinyl alcohol being attached to polysaccharide support.
 7. Thecomposition of claim 6, wherein the AP is present in a concentration of1 μg-100 mg/ml.
 8. The composition of claim 6, wherein the polyvinylalcohol carrier has 200-600 monomeric units.